ABSTRACT
Inactivation of the VHL tumour suppressor gene is a highly frequent genetic event in the carcinogenesis of central nervous system-(CNS) hemangioblastomas (HBs). The patterning of the similar embryonic vasculogenesis is an increasing concern in HB-neovascularization, and the classic vascular endothelial growth factor (VEGF)-mediated angiogenesis driven by VHL loss-of-function from human endothelium have been questioned. With this regard, we identify a distinct, VHL silencing-driven mechanism in which human vascular endothelial cells by means of increasing cell proliferation and decreasing cell apoptosis, is concomitant with facilitating accumulation of Twist1 protein in vascular endothelial cells in vitro. Importantly, this molecular mechanism is also pinpointed in CNS-HBs, and associated with the process of HB-neovascularization. In contrast with recent studies of HB-neovascularization, these modified cells did not endow with the typical features of vasculogenesis, indicating that this is a common angiogenesis implementing the formation of the vascular network. Taken together, these findings suggest that vasculogenesis and angiogenesis may constitute complementary mechanisms for HB-neovascularization, and could provide a rational recognition of single anti-angiogenic intervention including targeting to the Twist1 signalling for HBs.
Subject(s)
Cerebellar Neoplasms/genetics , Gene Expression Regulation, Neoplastic , Hemangioblastoma/genetics , Neovascularization, Pathologic/genetics , Nuclear Proteins/genetics , Twist-Related Protein 1/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Adolescent , Adult , Aged , Apoptosis , Cell Cycle/genetics , Cell Line, Tumor , Cell Proliferation , Cerebellar Neoplasms/blood supply , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/pathology , Female , Gene Expression Profiling , Gene Ontology , HEK293 Cells , Hemangioblastoma/blood supply , Hemangioblastoma/metabolism , Hemangioblastoma/pathology , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Male , Middle Aged , Molecular Sequence Annotation , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Nuclear Proteins/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Twist-Related Protein 1/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/antagonists & inhibitors , Von Hippel-Lindau Tumor Suppressor Protein/metabolismABSTRACT
OBJECTIVE: To study the changes of cat cerebral microcirculation in early stage after craniocerebral gunshot wound in the hot and humid environment to provide laboratory evidence for clinical treatment of such wound. METHODS: Craniocerebral gunshot wound was induced in 24 cats according to the method described by Carey with modifications, and the cats were placed in a cabin with environmental temperature and humidity of 25 degrees Celsius and 50% (group A), and 35 degrees Celsius and 85% (group B), respectively, to observe the changes in all the indices of cerebral microcirculation. RESULTS: All the cats survived and notable changes occurred in the morphology and permeability of cerebral microvascular along with obvious pathological changes in the brain tissue, and the vital signs, hemorheology and blood-brain barrier were significantly different between groups A and B. CONCLUSION: Hot and humid environment induces obvious changes in cat cerebral microcirculation and blood-brain barrier function in the early stages after craniocerebral gunshot wound.
